Asymmetric ‘Clip-Cycle’ Synthesis of Pyrrolidines and Spiropyrrolidines

Paul Andrew Clarke, Kristaps Ermanis, Christopher Maddocks

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The development of an asymmetric ‘clip-cycle’ synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activated by ‘clipping’ them to thioacrylate via an al-kene metathesis reaction. Enantioselective intramolecular aza-Michael cyclisation onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reac-tion accommodated a range of substitution to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ke-tone and oxoester-containing substrates. DFT studies sup-ported the aza-Michael cyclisation as the rate and stereo-chemical determining step, and correctly predicted the for-mation of the major enantiomer. The catalytic asymmetric syntheses of N-methyl pyrrolidine alkaloids (R)-irnidine and (R)-bgugaine, which possess DNA binding and antibacterial properties were achieved using the ‘clip-cycle’ methodology.
Original languageEnglish
Pages (from-to)8116-8121
Number of pages6
JournalOrganic Letters
Early online date29 Sept 2020
Publication statusPublished - 16 Oct 2020

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